Nociceptors are primary sensory afferent (C and Aδ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH<6) modalities. The lipophilic vanilloid, capsaicin, activates primary sensory fibers via a specific cell surface capsaicin receptor, cloned as the transient receptor potential vanilloid-1 (TRPV1). TRPV1 is also known as vanilloid receptor-1 (VR1). The intradermal administration of capsaicin is characterized by an initial burning or hot sensation followed by a prolonged period of analgesia. It is believed that the analgesic component of the TRPV1 receptor activation is mediated by a capsaicin-induced desensitization of the primary sensory afferent terminal. Thus, the long lasting anti-nociceptive effect of capsaicin has prompted the clinical use of capsaicin analogs as analgesic agents. Further, capsazepine, a capsaicin receptor antagonist can reduce inflammation-induced hyperalgesia in animal models. TRPV1 receptors are also localized on sensory afferents, which innervate the bladder. Capsaicin or resiniferatoxin has been shown to ameliorate incontinence symptoms upon injection into the bladder.
The TRPV1 receptor has been called a “polymodal detector” of noxious stimuli since it can be activated in several ways. The receptor channel is activated by capsaicin and other vanilloids, and thus is classified as a ligand-gated ion channel. TRPV1 receptor activation by capsaicin can be blocked by the competitive TRPV1 receptor antagonist, capsazepine. Protons (acidic pH) can also activate the TRPV1 channel. Under mildly acidic conditions (pH 6-7), the affinity of capsaicin for the receptor is increased, whereas at pH<6, direct activation of the channel occurs. In addition, when membrane temperature reaches 43° C., the channel is opened. Thus heat can directly gate the channel in the absence of ligand. The capsaicin analog, capsazepine, which is a competitive antagonist of capsaicin, blocks activation of the channel in response to capsaicin, acid, or heat.
The channel is a nonspecific cation conductor. Both extracellular sodium and calcium enter through the channel pore, resulting in cell membrane depolarization. This depolarization increases neuronal excitability, leading to action potential firing and transmission of a noxious nerve impulse to the spinal cord. In addition, depolarization of the peripheral terminal can lead to release of inflammatory peptides such as, but not limited to, substance P and CGRP, leading to enhanced peripheral sensitization of tissue.
Recently, two groups have reported the generation of a “knockout” mouse lacking the TRPV1 receptor. Electrophysiological studies of sensory neurons (dorsal root ganglia) from these animals revealed a marked absence of responses evoked by noxious stimuli including capsaicin, heat, and reduced pH. These animals did not display any overt signs of behavioral impairment and showed no differences in responses to acute non-noxious thermal and mechanical stimulation relative to wild-type mice. The TRPV1 (−/−) mice also did not show reduced sensitivity to nerve injury-induced mechanical or thermal nociception. However, the TRPV1 knockout mice were insensitive to the noxious effects of intradermal capsaicin, exposure to intense heat (50-55° C.), and failed to develop thermal hyperalgesia following the intradermal administration of carrageenan.
TRPV1 receptors have been found in both the peripheral nervous system and the central nervous system (CNS). In the brain, TRPV1 receptors have been identified in various regions known for their role in pain transmission or modulation (Merzey et al., Proc. Natl. Acad. Sci. USA 97:3655-3660 (2000); Szabo et al., Mol. Brain. Res. 98:51-57 (2002); Roberts et al., Brain Res. 995:176-183 (2004)). Using TRPV1 antagonists with similar in vitro potency but different CNS penetration, studies by Cui, M.; Honore, P. et al. J. Neuroscience 26:9385-9393 (2006) demonstrated that the CNS plays a differential role in the effect of TRPV1 antagonists in various types of pain. Employing a number of rodent models, these experiments showed that TRPV1 receptors in the CNS play an important role in pain mediated by central sensitization. Moreover, these findings demonstrated that significant CNS penetration is necessary for a TRPV1 antagonist to produce broad-spectrum analgesia.
Certain TRPV1 antagonists are discussed in U.S. Publication No. 2006/0281799 with unknown CNS penetration. Accordingly, the need exists to develop TRPV1 antagonists that exhibit good CNS penetration. Such antagonists may provide full efficacy across a wide array of pain states.
We herein describe series of TRPV1 antagonists with CNS penetration.